Vol 55, No 5 (2021)
Research Paper
Published online: 2021-10-19

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Does granulocyte-colony stimulating factor stimulate peripheral nerve regeneration? An experimental study on traumatic lesion of the sciatic nerve in rats

Doerthe Keiner1, Harald von Pein2, Jacek Szczygielski13, Andreas Kramer4, Axel Heimann5, Oliver Kempski5, Clemens Sommer2, Joachim Oertel1
Pubmed: 34664711
Neurol Neurochir Pol 2021;55(5):469-478.

Abstract

Aim of the study. To analyse the therapeutic potential of granulocyte-colony stimulating factor (G-CSF) treatment using a rat model of traumatic sciatic nerve lesion. Clinical rationale for the study. G-CSF has proven strong neurotrophic properties in various models of ischaemic and traumatic brain injury. Fewer studies exist regarding the influence of G-CSF on posttraumatic peripheral nerve regeneration. Currently, the possibilities of pharmacological prevention or treatment of mechanical nerve injury are limited, and there is an urgent need to find new treatment strategies applicable in clinical situations. Material and methods. A controlled traumatic right sciatic nerve lesion was set using a waterjet device. Three treatment groups were created. In the first group, G-CSF was administered after sciatic nerve injury. The second group received G-CSF before and after trauma, while the third group was treated with glucose 5%-solution. Sciatic nerve function was assessed clinically and electrophysiologically at day 1, and after weeks 1, 2, 4 and 6. Additionally, α-motoneurons of the spinal cord and sciatic nerve fibres were counted at week 6. Results. Clinically, rats in both G-CSF groups improved faster compared to the control group. Additionally, animals treated with G-CSF had a significantly better improvement of motor potential amplitude and motor nerve conduction velocity at week 6 (p < 0.05). Histologically, G-CSF treatment resulted in a significantly higher number of α-motoneurons and small myelinated nerve fibres compared to placebo treatment (p < 0.05). Conclusions and clinical implications. Under G-CSF treatment, the recovery of motor nerve conduction velocity and amplitude was enhanced. Further, signs of nerve regeneration and preservation of α-motoneurons were observed. These results indicate that G-CSF might accelerate and intensify the recovery of injured nerves. Thus, treatment with G-CSF may be beneficial for patients with peripheral nerve damage, and should be explored in further clinical studies.

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References

  1. Schneider A, Krüger C, Steigleder T, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest. 2005; 115(8): 2083–2098.
  2. Strecker JK, Sevimli S, Schilling M, et al. Effects of G-CSF treatment on neutrophil mobilization and neurological outcome after transient focal ischemia. Exp Neurol. 2010; 222(1): 108–113.
  3. Schäbitz WR, Schneider A. New targets for established proteins: exploring G-CSF for the treatment of stroke. Trends Pharmacol Sci. 2007; 28(4): 157–161.
  4. Pan HC, Wu HT, Cheng FC, et al. Potentiation of angiogenesis and regeneration by G-CSF after sciatic nerve crush injury. Biochem Biophys Res Commun. 2009; 382(1): 177–182.
  5. Diederich K, Quennet V, Bauer H, et al. Successful regeneration after experimental stroke by granulocyte-colony stimulating factor is not further enhanced by constraint-induced movement therapy either in concurrent or in sequential combination therapy. Stroke. 2012; 43(1): 185–192.
  6. Gibson CL, Bath PMW, Murphy SP. G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2005; 25(4): 431–439.
  7. Lee ST, Chu K, Jung KH, et al. Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Res. 2005; 1058(1-2): 120–128.
  8. Schäbitz WR, Schneider A. Developing granulocyte-colony stimulating factor for the treatment of stroke: current status of clinical trials. Stroke. 2006; 37(7): 1654; author reply 1655.
  9. Henriques A, Pitzer C, Dupuis L, et al. G-CSF protects motoneurons against axotomy-induced apoptotic death in neonatal mice. BMC Neurosci. 2010; 11: 25.
  10. Pitzer C, Krüger C, Plaas C, et al. Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis. Brain. 2008; 131(Pt 12): 3335–3347.
  11. Oertel J, Gaab MR, Knapp A, et al. Water jet dissection in neurosurgery: experimental results in the porcine cadaveric brain. Neurosurgery. 2003; 52(1): 153–9; discussion 159.
  12. Oertel J, Gaab MR, Piek J. Waterjet resection of brain metastases - first clinical results with 10 patients. Eur J Surg Oncol. 2003; 29(4): 407–414.
  13. Oertel J, Gaab MR, Pillich DT, et al. Comparison of waterjet dissection and ultrasonic aspiration: an in vivo study in the rabbit brain. J Neurosurg. 2004; 100(3): 498–504.
  14. Oertel J, Gaab MR, Runge U, et al. Waterjet dissection versus ultrasonic aspiration in epilepsy surgery. Neurosurgery. 2005; 56(1 Suppl): 142–6; discussion 142.
  15. Oertel J, Gaab MR, Warzok R, et al. Waterjet dissection in the brain: review of the experimental and clinical data with special reference to meningioma surgery. Neurosurg Rev. 2003; 26(3): 168–174.
  16. Piek J, Oertel J, Gaab MR. Waterjet dissection in neurosurgical procedures: clinical results in 35 patients. J Neurosurg. 2002; 96(4): 690–696.
  17. Piek J, Wille C, Warzok R, et al. Waterjet dissection of the brain: experimental and first clinical results. Technical note. J Neurosurg. 1998; 89(5): 861–864.
  18. Keiner D, Gaab MR, Backhaus V, et al. Water jet dissection in neurosurgery: an update after 208 procedures with special reference to surgical technique and complications. Neurosurgery. 2010; 67(2 Suppl Operative): 342–354.
  19. Tschan C, Gaab MR, Krauss JK, et al. Waterjet dissection of the vestibulocochlear nerve: an experimental study. J Neurosurg. 2009; 110(4): 656–661.
  20. Tschan CA, Keiner D, Müller HD, et al. Waterjet dissection of peripheral nerves: an experimental study of the sciatic nerve of rats. Neurosurgery. 2010; 67(2 Suppl Operative): 368–376.
  21. Dinh P, Hazel A, Palispis W, et al. Functional assessment after sciatic nerve injury in a rat model. Microsurgery. 2009; 29(8): 644–649.
  22. Kalender AM, Dogan A, Bakan V, et al. Effect of Zofenopril on regeneration of sciatic nerve crush injury in a rat model. J Brachial Plex Peripher Nerve Inj. 2009; 4: 6.
  23. Yan JG, Matloub HS, Yan Y, et al. The correlation between calcium absorption and electrophysiological recovery in crushed rat peripheral nerves. Microsurgery. 2010; 30(2): 138–145.
  24. Kouyoumdjian JA. Peripheral nerve injuries: a retrospective survey of 456 cases. Muscle Nerve. 2006; 34(6): 785–788.
  25. Eser F, Aktekin LA, Bodur H, et al. Etiological factors of traumatic peripheral nerve injuries. Neurol India. 2009; 57(4): 434–437.
  26. Kretschmer T, Antoniadis G, Braun V, et al. Evaluation of iatrogenic lesions in 722 surgically treated cases of peripheral nerve trauma. J Neurosurg. 2001; 94(6): 905–912.
  27. Wee AS, Truitt NR, Smith LD. Type and frequency of peripheral nerve injuries encountered in a clinical neurophysiology laboratory. Journal of the Mississippi State Medical Association. 2006; 47: 67–71.
  28. de Medinaceli L, Freed WJ, Wyatt RJ. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp Neurol. 1982; 77(3): 634–643.
  29. McGrath AM, Brohlin M, Kingham PJ, et al. Fibrin conduit supplemented with human mesenchymal stem cells and immunosuppressive treatment enhances regeneration after peripheral nerve injury. Neurosci Lett. 2012; 516(2): 171–176.
  30. Imaizumi K, Benito A, Kiryu-Seo S, et al. Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death. J Neurosci. 2004; 24(15): 3721–3725.
  31. Belkas JS, Munro CA, Shoichet MS, et al. Long-term in vivo biomechanical properties and biocompatibility of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) nerve conduits. Biomaterials. 2005; 26(14): 1741–1749.
  32. Kemp SWP, Webb AA, Dhaliwal S, et al. Dose and duration of nerve growth factor (NGF) administration determine the extent of behavioral recovery following peripheral nerve injury in the rat. Exp Neurol. 2011; 229(2): 460–470.
  33. Alrashdan MS, Sung MA, Kwon YK, et al. Effects of combining electrical stimulation with BDNF gene transfer on the regeneration of crushed rat sciatic nerve. Acta Neurochir (Wien). 2011; 153(10): 2021–2029.
  34. Devesa P, Gelabert M, Gonźlez-Mosquera T, et al. Growth hormone treatment enhances the functional recovery of sciatic nerves after transection and repair. Muscle Nerve. 2012; 45(3): 385–392.
  35. Haastert-Talini K, Schmitte R, Korte N, et al. Electrical stimulation accelerates axonal and functional peripheral nerve regeneration across long gaps. J Neurotrauma. 2011; 28(4): 661–674.
  36. Ridwan S, Bauer H, Frauenknecht K, et al. Distribution of granulocyte-monocyte colony-stimulating factor and its receptor α-subunit in the adult human brain with specific reference to Alzheimer's disease. J Neural Transm (Vienna). 2012; 119(11): 1389–1406.
  37. Minnerup J, Sevimli S, Schäbitz WR. Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies. Exp Transl Stroke Med. 2009; 1: 2.
  38. Perrelet D, Ferri A, MacKenzie AE, et al. IAP family proteins delay motoneuron cell death in vivo. Eur J Neurosci. 2000; 12(6): 2059–2067.
  39. Lee AC, Yu VM, Lowe JB, et al. Controlled release of nerve growth factor enhances sciatic nerve regeneration. Exp Neurol. 2003; 184(1): 295–303.